The present invention is directed to compounds, and methods using such compounds, that when administered to an animal, arrest the inflammatory response in affected tissues and facilitate repair and maintenance of damaged tissues in the joints of vertebrates.
In healthy conditions, articular cartilage forms a smooth surface between articulating bone ends to reduce the friction caused by movement. This friction is further reduced by the synovial fluid.
Articular cartilage consists of chondrocytes and two major macro-molecules; i.e., collagen and proteoglycans, which are synthesized by and deposited around the chondrocytes. The chondrocytes also synthesize the synovial fluid which bathes the articular cartilage.
The structural integrity of the articular cartilage is the foundation of optimal functioning of the skeletal joints in the hip, shoulders, elbows, hocks and stifles. Impaired function of skeletal joints will dramatically reduce mobility such as rising from sitting position or climbing and descending stairs.
To maintain the structural integrity and the proper functioning of the articular cartilage, the chondrocytes constantly synthesize collagen and proteoglycans, the major components of the articular cartilage, as well as the friction-reducing synovial fluid. This constant synthesis of the macro-molecules and synovial fluid provides the articular cartilage with the repairing mechanism for most of the wearing caused by friction between the bone ends. However, it also leads to the constant demand for the supply of precursors, or building blocks, for the macromolecules and synovial fluid. Lack of this precursors will lead to defects in the structure and function of the skeletal joints. This deficiency occurs often when activity levels are very high, or cartilage tissue has been traumatized.
An adequate supply of metabolic precursors or building blocks is thus paramount to replacement and repair of the constituents of skeletal joints, connective tissue and synovial fluid. Proteoglycans (or mucopolysaccharides) form the ground substance of cartilage, bone and joint fluid. Proteoglycans are comprised of proteins linked to glycosaminoglycans (GAGs). The building block GAG subunit of the proteoglycan in cartilage and bone is chondroitin sulfate. Chondroitin sulfate A is present in cornea and cartilage. Chondroitin sulfate B (G-heparin) is found in tendon, aorta, skin and heart valves. Chondroitin C is found in cartilage, tendon and umbilical cord and similar tissues. The building block GAG subunit of the proteoglycan in joint fluid is hyaluronic acid. Intercellular solutions of hyaluronic acid are viscous and thus assist in lubrication of the joints of body skeleton. Hyaluronic acid is synthesized from the metabolic precursor, glucosamine. The availability of glucosamine in cartilage tissue can be rate-limiting to the enzymatic step leading to the production of proteoglycans. Exogenous glucosamine serves to drive the biosynthetic pathway forward past the rate-limiting blockage point. Glucosamine serves as a substrate for a kinase enzyme which yields glucosamine-6-phosphate, the rate-limiting precursor in proteoglycan synthesis. Recently, studies have reported the suppression of autoimmune disorders such as rheumatoid arthritis upon ingestion of cartilage fibers derived from chickens and sharks. The therapy, termed oral tolerization, is not fully understood but it is theorized that a mechanism in the digestive tract disarms immune cells that would otherwise assault food molecules as foreign intruders to the body, akin to foreign substances that enter the blood stream by means other than the gastrointestinal tract. Apparently, the immune-disarming effect occurs not only in the gut, but also in the vulnerable tissues.
Numerous disclosures describe therapy of damaged tissues by introduction of precursors in the metabolic pathway leading to biosynthesis of the macromolecules of connective tissues. For example, in U.S. Pat. No. 3,697,652 (Rovati et al.), N-acetylglucosamine is used to treat degenerative afflictions of the joints. In U.S. Pat. No. 3,683,076 (Rovati et al.), glucosamine salts are described as pharmaceutically useful for treatment of osteoarthritis and rheumatoid arthritis. U.S. Pat. Nos. 4,647,453 (Meisner) and 4,772,591 (Meisner) disclose the use of glucosamine salts for treatment of degenerative inflammatory disease and as a means of accelerating wound healing. In U.S. Pat. No. 4,801,619 (Lindblad), a hyaluronic acid preparation is claimed to be effective for treatment of steroid arthropathy and progressive cartilage degeneration caused by proteoglycan degradation. A combination of glucosamine, chondroitin and manganese is claimed in U.S. Pat. No. 5,364,845 (Henderson) as a means of protecting and repair of connective tissue. None of these prior investigators, however, disclose a composition having metabolic precursors, herbal phytochemicals and palatability agents that work synergistically to prevent and treat joint and connective tissue disorders.
The present invention relates to prophylaxis and therapy of joint disorders in vertebrates accomplished by oral administration of a combination of natural physiological metabolites and herbal phytochemicals. Arthritic disorders, including rheumatism, osteoarthritis, dysplasia, lupus, bursitis and gout, are all characterized by inflammation and pain in joints, muscles and related connective tissues. Most of the forms are progressive. The present inventors disclose for the first time herein a synergistic effect of the natural physiological metabolites and herbal phytochemicals for treatment of joint disorders in vertebrates.
The present invention is directed to a composition capable of eliminating or diminishing inflammation are in accelerating the tissue repair process. Even though prior investigators used anti-inflammatory substances, their compositions did not provide a complete array of necessary repair and maintenance precursor building blocks along with anti-inflammatory substances. Furthermore, the anti-inflammatory substances utilized by prior investigators are not comprised of natural herbal phytochemicals. In fact, it is known that some substances which exhibit anti-inflammatory responses, such as glucosamine, do not exert general activity. Instead, the response may be mediator specific. Thus, one aspect of the present invention relates to the provision of multiple anti-inflammatory herbal phytochemicals that have more general reactivity and, hence, are more efficacious in a broader population.
One aspect of the present invention relates to a composition of chondroitin sulfate and glucosamine to provide the necessary building blocks and biosynthetic regulation for repair and maintenance of cartilage, bone, tendon and joint lubricating fluids. It is believed that ingestion of cartilage or connective tissue precursor building blocks such as chondroitin may elicit the same oral tolerance effects, thus suppressing the degradation of connective tissue by an autoimmune response. For chondroprotective agents such as chondroitin sulfate and glucosamine to be efficacious when orally administered, it is important that they be absorbed from the intestinal tract without change in their chemical structure. Studies have confirmed that both chondroitin sulfate and glucosamine are absorbed without modification of their molecular structure.
The present invention is also directed to the use of antioxidants in the control of inflammation and its degradative effects on connective tissue. Oxygen-derived free radicals apparently act as mediators of inflammation and/or tissue destruction in inflammatory and arthritic disorders. Free radicals degrade synovial fluid hyaluronic acid, modify collagen and perhaps proteoglycan structure and/or synthesis, alter and interact with immunoglobulins, activate degradative enzymes and inactivate their inhibitors, and possibly participate in chemotaxis. The present invention thus relates to a composition containing antioxidants that are advantageous in that the free radicals are scavenged and detoxified before they reach the affected area.
Prior investigators also failed to disclose a means of increasing circulation to the affected area. The present invention therefore relates to increasing circulation to accelerate the repair process by removal of deleterious inflammatory substances and by providing copious quantities of precursor building blocks for repair and maintenance.
One aspect of the present invention is directed to compositions containing ingredients that enhance the absorption of necessary repair precursors from the gastrointestinal tract. Another aspect relates to a means of enhancing the oral palatability of such composition. Clearly, compliance is necessary to ensure proper dosage of active ingredients necessary for therapeutic functions. Ingestion of the total dosage regimen is even more dependent on palatability in animals who only voluntarily consume oral compositions if they are presented with an acceptable flavor.
Therefore, the present invention is intended to provide a means of accelerating the repair of arthritic tissues by provision of metabolic precursor building blocks, herbal phytochemicals and palatability agents. This combination has synergistic advantages over previously known compositions. As disclosed in more detail in the detailed description of the invention and the appended figures, the present invention provides a composition and method for treating various joint disorders in vertebrates utilizing the synergistic combination of natural physiological metabolites and herbal phytochemicals, together with palatability agents.